Combinations of SSRI and estrogenic agents

ABSTRACT

This invention comprises methods of depression, anxiety, generalized anxiety disorder (GAD), hot flush, post partum depression, premenstrual syndrome, obesity, obsessive compulsive disorder, post-traumatic stress disorder, social phobia, disruptive behavior disorders, impulse control disorders, borderline personality disorder, chronic fatigue disorder, premature ejaculation, pain, attention deficit disorders, with and without hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa, or Shy Drager Syndrome comprising administration of a selective serotonin reuptake inhibitor and compound of the formulae I or II:  
                 
 
     wherein Z is a moiety selected from the group of:  
                 
 
     wherein: R 1  is selected from H, OH or the C 1 -C 12  esters or C 1 -C 12  alkyl ethers thereof, benzyloxy, or halogen; or C 1 -C 4  halogenated ethers including trifluoromethyl ether and trichloromethyl ether; R 2 , R 3 , R 4 , R 5 , and R 6  are H, OH or C 1 -C 12  esters or C 1 -C 12  alkyl ethers thereof, halogens, or C 1 -C 4  halogenated ethers, cyano, C 1 -C 6  alkyl, or trifluoromethyl, with the proviso that, when R 1  is H, R 2  is not OH; Y is the moiety:  
                 
 
     R 7  and R 8  are alkyl or concatenated together to form an optionally substituted, nitrogen-containing ring; or a pharmaceutically acceptable salt thereof.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/216,408, filed Jul. 6, 2000.

[0002] This invention relates to methods of using substituted indolecompounds in the combination with a selective serotonin reuptakeinhibitor (SSRI) for the treatment, prevention, inhibition oralleviation of depression, anxiety, generalized anxiety disorder (GAD),hot flush, post partum depression, premenstrual syndrome, obesity,obsessive compulsive disorder, social phobia, disruptive behaviordisorders, impulse control disorders, borderline personality disorder,chronic fatigue disorder, premature ejaculation, pain, post-traumaticstress disorder, attention deficit disorders, with and withouthyperactivity, Gilles de la Tourette syndrome, bulimia nervosa, or ShyDrager Syndrome and related pharmaceutical compositions and kits.

BACKGROUND OF THE INVENTION

[0003] EP 0 802 183 A1 and U.S. Pat. No. 5,780,497 describe substitutedindole compounds of the formulae below:

[0004] as well as their use as estrogenic agents, including thetreatment of bone loss, cardiovascular disease, maladies associated withor resulting from the proliferation or abnormal development ofendometrial or endometrial-like tissues, and disease states or syndromesassociated with estrogen deficiency.

[0005] EP 0 802 184 A1, published Oct. 22, 1997, describes comparableuses for substituted indole compounds of the formulae below.

[0006] Analogous indole compounds having the general structures:

[0007] are described in U.S. Pat. No. 5,880,137 (Miller et al.).

[0008] Filipponi P et al: Cyclical clodronate is effective in preventingpostmenopausal bone loss: A comparative study with transcutaneoushormone replacement therapy. J Bone Min Res 10:697-703, 1995.

[0009] DESCRIPTION OF THE INVENTION

[0010] This invention comprises methods of treating, preventing,alleviating or inhibiting depression, anxiety, generalized anxietydisorder (GAD), hot flush, post partum depression, premenstrualsyndrome, obesity, obsessive compulsive disorder, post-traumatic stressdisorder, social phobia, disruptive behavior disorders, impulse controldisorders, borderline personality disorder, chronic fatigue disorder,premature ejaculation, pain, attention deficit disorders, with andwithout hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa,or Shy Drager Syndrome in a mammal, preferably in a human, the methodscomprising administering to a mammal in need thereof a pharmaceuticallyeffective combination of:

[0011] a) a pharmaceutically effective amount of a selective serotoninreuptake inhibitor (SSRI), or a pharmaceutically effective salt thereof;and

[0012] b) a pharmaceutically effective amount of a substituted indolecompound of the formulae I or II, below:

[0013] wherein Z is a moiety selected from the group of:

[0014] wherein:

[0015] R₁ is selected from H, OH or the C₁-C₁₂ esters (straight chain orbranched) or C₁-C₁₂ (straight chain or branched or cyclic) alkyl ethersthereof, benzyloxy, or halogens; or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether.

[0016] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters (straight chain or branched) or C₁-C₁₂ alkyl ethers(straight chain or branched or cyclic) thereof, halogens, or C₁-C₄halogenated ethers including trifluoromethyl ether and trichloromethylether, cyano, C₁-C₆ alkyl (straight chain or branched), ortrifluoromethyl, with the proviso that, when R₁ is H, R₂ is not OH;

[0017] R₄ is selected from H, OH or the C₁-C₁₂ esters (straight chain orbranched) or C₁-C₁₂ alkyl ethers (straight chain or branched or cyclic)thereof, benzyloxy, halogens, or C₁-C₄ halogenated ethers includingtrifluoromethyl ether and trichloromethyl ether, cyano, C₁-C₆ alkyl(straight chain or branched), or trifluoromethyl;

[0018] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0019] n is 1, 2 or 3;

[0020] Y is selected from:

[0021] a) the moiety:

[0022] wherein R₇ and R₈ are independently selected from the group of H,C₁-C₆ alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl(straight chain or branched), C₁-C₆ alkoxy (straight chain or branched),halogen, —OH, —CF₃, or —OCF₃;

[0023] b) a five-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁C₄ alkyl)-, —N═, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl;

[0024] c) a six-membered saturated, unsaturated or partially unsaturatedheterocycle containing up to two heteroatoms selected from the groupconsisting of —O—, —NH—, —N(C₁C₄ alkyl)-, —N═, and —S(O)_(m)—, wherein mis an integer of from 0-2, optionally substituted with 1-3 substituentsindependently selected from the group consisting of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl;

[0025] d) a seven-membered saturated, unsaturated or partiallyunsaturated heterocycle containing up to two heteroatoms selected fromthe group consisting of —O—, —NH—, —N(C₁C₄ alkyl)-, —N═, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄)alkyl; or

[0026] e) a bicyclic heterocycle containing from 6-12 carbon atomseither bridged or fused and containing up to two heteroatoms selectedfrom the group consisting of —O—, —NH—, —N(C₁C₄ alkyl)-, and —S(O)_(m)—,wherein m is an integer of from 0-2, optionally substituted with 1-3substituents independently selected from the group consisting ofhydrogen, hydroxyl, halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy,trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—,—NH₂—, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂,and phenyl optionally substituted with 1-3 (C₁-C₄) alkyl;

[0027] and the pharmaceutically acceptable salts thereof.

[0028] The more preferred substituted indole compounds of this inventionare those having the general structures I or II, above, wherein:

[0029] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, or halogen;

[0030] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrihalomethyl, preferably trifluoromethyl, with the proviso that, whenR₁ is H, R₂ is not OH;

[0031] R₄ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl;

[0032] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0033] Y is the moiety

[0034] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)_(p)—, wherein p is an integer of from 2 to 6, so asto form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃;

[0035] and the pharmaceutically acceptable salts thereof.

[0036] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0037] The most preferred substituted indole compounds of the presentinvention are those having the structural formulas I or II, above,wherein R₁ is OH; R₂-R₆ are as defined above; X is selected from thegroup of Cl, NO₂, CN, CF₃, or CH₃; and Y is the moiety

[0038] and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0039] and the pharmaceutically acceptable salts thereof.

[0040] In another embodiment of this invention, when R₇ and R₈ areconcatenated together as —(CH₂)_(p)—, wherein p is an integer of from 2to 6, preferably 4 to 6, the ring so formed is optionally substitutedwith 1-3 substituents selected from a group containing C₁-C₃ alkyl,trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

[0041] The invention includes sulfate, sulfamates and sulfate esters ofphenolic groups of the substituted indoles. Sulfates can be readilyprepared by the reaction of the free phenolic compounds with sulfurtrioxide complexed with an amine such as pyridine, trimethylamine,triethylamine, etc. Sulfamates can be prepared by treating the freephenolic compound with the desired amino or alkylamino or dialkylaminosulfamyl chloride in the presence of a suitable base such as pyridine.Sulfate esters can be prepared by reaction of the free phenol with thedesired alkanesulfonyl chloride in the presence of a suitable base suchas pyridine. Additionally, this invention includes compounds containingphosphates at the phenol as well as dialkyl phosphates. Phosphates canbe prepared by reaction of the phenol with the appropriatechlorophosphate. The dialkylphosphates can be hydrolyzed to yield thefree phosphates. Phosphinates are also claimed where the phenol isreacted with the desired dialkylphosphinic chloride to yield the desireddialkylphosphinate of the phenol.

[0042] The invention includes acceptable salt forms of the substitutedindole formed from the addition reaction with either inorganic ororganic acids. Inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric aciduseful as well as organic acids such as acetic acid, propionic acid,citric acid, maleic acid, malic acid, tartaric acid, phthalic acid,succinic acid, methanesulfonic acid, toluenesulfonic acid,napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid areuseful. It is known that compounds possessing a basic nitrogen can becomplexed with many different acids (both protic and non-protic) andusually it is preferred to administer a compound of this invention inthe form of an acid addition salt. Additionally, this invention includesquaternary ammonium salts of the compounds herein. These can be preparedby reacting the nucleophilic amines of the side chain with a suitablyreactive alkylating agent such as an alkyl halide or benzyl halide.

[0043] The present invention includes methods for treating pain usingthe combinations described herein. Pain in these instances includes, butis not limited to, neuropathic pain, chronic pain, musculoskeletal pain,cancer pains, fibromyalgia, psychogenic pain, neurogenic pain, facialneuralgias and pain associated with shingles.

[0044] These methods each comprise administering to a mammal in needthereof a pharmaceutically effective amount of a SSRI agent and apharmaceutically effective amount of one of the substituted indolestaught herein, or a pharmaceutically acceptable salt of either of theseagents. These administrations may be therapeutic or prophylactic. Amongthe preferred substituted indole compounds for use in these methods are1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol,also known as TSE-424, and2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol,also known as ERA-923.

[0045] SSRI agents useful with the present methods of treatment include,but are not limited to, venlafaxine, fluoxetine, paroxetine, sertraline,or fluvoxamine, or a pharmaceutically acceptable salt thereof.

[0046] The present invention includes methods utilizing in conjunctionwith a SSRI compound a first subset or subgroup of substituted indolecompounds of the formulas III or IV, below:

[0047] wherein the variable substituents including R₁, R₂, R₃, R₄, R₅,R₆, n, X, and Y are as defined above, or a pharmaceutically acceptablesalt thereof.

[0048] The more preferred substituted indole compounds of this firstsubset of compounds are those having the general structures III or IV,above, wherein:

[0049] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, or halogen;

[0050] R₂, R₃, R₅, and R₆ are independently selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano, C₁-C₆ alkyl, ortrihalomethyl, preferably trifluoromethyl, with the proviso that, whenR₁ is H, R₂ is not OH;

[0051] R₄ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, benzyloxy, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl;

[0052] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0053] Y is the moiety

[0054] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)_(p)—, wherein p is an integer of from 2 to 6, so asto form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃; and the pharmaceuticallyacceptable salts thereof.

[0055] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0056] The most preferred substituted indole compounds of this firstsubset of compounds are those having the structural formulas I or II,above, wherein R₁ is OH; R₂-R₆ are as defined above; X is selected fromthe group of Cl, NO₂, CN, CF₃, or C₃; and Y is the moiety

[0057] and R₇ and R₈ are concatenated together as —(CH₂)_(r), wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0058] and the pharmaceutically acceptable salts thereof.

[0059] In another embodiment of this first subset of compounds, when R₇and R₈ are concatenated together as —(CH₂)_(p)—, wherein p is an integerof from 2 to 6, preferably 4 to 6, the ring so formed is optionallysubstituted with 1-3 substituents selected from a group containing C₁-C₃alkyl, trifluoromethyl, halogen, hydrogen, phenyl, nitro, —CN.

[0060] Among the preferred compounds of this first subset of substitutedindoles are the following:

[0061]5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0062]5-Benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0063]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0064]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-diisopropylamino-1-yl-ethoxy)-benzyl]-lH-indole;

[0065]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-butyl-methylamino-1-ylethoxy)-benzyl]-1H-indole;

[0066]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-dimethylamino)-ethoxy]-benzyl}-1H-indole;

[0067]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0068]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0069]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0070]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0071]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indole;

[0072](1S,4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl{4-[2-(2-Aza-bicyclo[2.2.1] hept-2-yl)-ethoxy]-benzyl}-1H-indole;

[0073]5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0074]5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0075]5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0076]5-Benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0077]5-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0078]5-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0079]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole;

[0080]5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0081]5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0082]5-Benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indole;

[0083]5-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole;

[0084](2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethyl)-cyclohexyl-amine;

[0085]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylpiperazin-1-yl)-ethoxy]-benzyl}-1H-indole;

[0086]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3-methyl-1H-indole;

[0087] 4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole};

[0088]4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol;

[0089]3-Methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0090]4-{5-Methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2-yl}-phenol;

[0091]2-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0092]5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0093]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole;

[0094]2-(4-Ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0095]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol-5-ol;

[0096]4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-phenol;

[0097]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol-5-ol;

[0098]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0099]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0100]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0101]1-[4-(2-Azocan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0102]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0103]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0104]1-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0105]1-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0106]1-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0107]1-{4-[2-(Butyl-methyl-amino)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-H-indol-5-ol;

[0108]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0109]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperdin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0110]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0111]1-{4-[2-(3,3-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0112]1-{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0113]2-(4-Hydroxy-phenyl)-1-{4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-benzyl}-3-methyl-1H-indol-5-ol;

[0114] (1S,4R)-1-{4-[2-(2-Aza-bicyclo [2.2.1]hept-2-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0115]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indol-5-ol;

[0116]2-(4-Fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0117]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol-5-ol;

[0118]2-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0119]2-Benzo[1,3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0120]2-(4-Isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0121]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-indol-5-ol;

[0122]2-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0123]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-phenyl)-1H-indol-5-ol;

[0124]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-p-tolyl-1H-indol-5-ol;

[0125]2-(4-Chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0126]2-(2,4-Dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0127]2-(3-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0128]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indole-5-ol;

[0129]2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0130]2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0131]2-(3-Methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-5-ol;

[0132]3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phenyl)-1H-indole-5-ol;

[0133]3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0134]3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0135]3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0136]3-Chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0137]2-(4-Hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl-1H-indol-5-ol;

[0138]5-Hydroxy-2-(4-Hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole-3-carbonitrile;

[0139]1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-1H-indole-3-cabonitrile;

[0140]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0141]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0142]5-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0143]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0144]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0145]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0146] Di-propionate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0147] Di-pivalate of1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol;

[0148]5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-3-methyl-1H-indole;

[0149]2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-indol-5-ol;

[0150]2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol;

[0151]2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methyl-1H-indol-5-ol;

[0152]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[3-Methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole;

[0153]5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[2-Methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole;

[0154]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol;

[0155] or the pharmaceutically acceptable salts thereof.

[0156] The compounds of this first subset or subgroup of compounds canbe produced by the methods described in EP 0 802 183 A1, published Oct.22, 1997, and U.S. Pat. No. 5,780,497, the subject matter of which isincorporated herein by reference, or by other methods known in the art.Aryloxy-alkyl-dialkylamines or aryloxy-alkyl-cyclic amines useful asintermediates in the production of the compounds above can be producedand used as disclosed in WO 99/19293, published Apr. 22, 1999, thesubject matter of which is also incorporated herein by reference.

[0157] A second subset or subgroup of substituted indole compoundsuseful with this invention includes those of formulas (V) or (VI),below:

[0158] wherein the variable substituents including R₁, R₂, R₃, R₄, R₅,R₆, n, X, and Y are as defined above, or a pharmaceutically acceptablesalt thereof.

[0159] Among the preferred substituted indole compounds of this secondsubset or subgroup are the following:

[0160](E)-N,N-Diethyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0161] 1(E)-N-tert-butyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0162](E)-Pyrollidino-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0163](E)-N,N-Dimethyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0164](E)-N,N-Dibutyl-3-[{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0165] (E)-N-Butyl,N′-methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0166](E)-Morpholinino-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-ylmethyl]-phenyl}-acrylamide;

[0167](E)-3-(4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl)-acrylamide;

[0168](E)-N,Methyl-3-{4-[5-hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}acrylamide;

[0169](E)-N,N-Dibutyl-3-{4-[5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0170](E)-N-Buty1,N′-Methyl-3-{4-[5-hydroxy-2-(4-fluoro-phenyl)-3-methyl-indol-1-ylmethyl]-phenyl}-acrylamide;

[0171] as well as the pharmaceutically acceptable salts and estersthereof.

[0172] The compounds of this second subset or subgroup of substitutedindole compounds can be produced by the methods described in EP 0 802184 A1, published Oct. 22, 1997, which is incorporated herein byreference, or by other methods known in the art.

[0173] A third subset of substituted indole compounds useful with thepresent invention include those of the formulae VII and VIII:

[0174] wherein n is 1, 2 or 3 and the variable substituents includingR₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined above, or apharmaceutically acceptable salt thereof.

[0175] Among the preferred compounds of this third subset of substitutedindoles are:

[0176]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-N,N-dimethyl-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;

[0177]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-piperidin-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;

[0178] and

[0179]2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-benzyl]-1H-indol-5-ol;

[0180] or pharmaceutically acceptable salts or esters thereof.

[0181] The compounds of this third subset or subgroup of substitutedindole compounds can be produced by the methods described in U.S. Pat.No. 5,880,137 (Miller et al.), which is incorporated herein byreference, or by other methods known in the art.

[0182] Within each of the first, second and third subsets of substitutedindole compounds of this invention are further subdivisions of morepreferred substituted indole compounds having the general structures Ithrough VIII, above, wherein:

[0183] R₁ is selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, halogen; R₂, R₃, R₄, RD5A, and R₆ are independently selectedfrom H, OH or the C₁-C₁₂ esters or alkyl ethers thereof, halogen, cyano,C₁-C₆ alkyl, or trihalomethyl, preferably trifluoromethyl, with theproviso that, when R₁ is H, R₂ is not OH;

[0184] X is selected from H, C₁-C₆ alkyl, cyano, nitro, trifluoromethyl,halogen;

[0185] Y is the moiety

[0186] R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, orcombined by —(CH₂)_(p)—, wherein p is an integer of from 2 to 6, so asto form a ring, the ring being optionally substituted by up to threesubstituents selected from the group of hydrogen, hydroxyl, halo, C₁-C₄alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H,—CN, —CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino,—NHSO₂(C₁-C₄), —NHCO(C₁-C₄), and —NO₃;

[0187] and the pharmaceutically acceptable salts thereof.

[0188] The rings formed by a concatenated R₇ and R₈, mentioned above,may include, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, hexamethyleneamine or heptamethyleneamine rings.

[0189] The most preferred substituted indole compounds of the presentinvention are those having the structural formulas I through VIII,above, wherein R₁ is OH; R₂-R₆ are as defined above; X is selected fromthe group of Cl, NO₂, CN, CF₃, or CH₃; and Y is the moiety

[0190] and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein ris an integer of from 4 to 6, to form a ring optionally substituted byup to three substituents selected from the group of hydrogen, hydroxyl,halo, C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂;

[0191] and the pharmaceutically acceptable salts thereof.

[0192] In another embodiment of the substituted indoles of thisinvention, when R₇ and R₈ are concatenated together as —(CH₂)_(p)—,wherein p is an integer of from 2 to 6, preferably 4 to 6, the ring soformed is optionally substituted with 1-3 substituents selected from agroup containing C₁-C₃ alkyl, trifluoromethyl, halogen, hydrogen,phenyl, nitro, —CN.

[0193] The invention includes sulfate, sulfamates and sulfate esters ofphenolic groups in these substituted indoles. Sulfates can be readilyprepared by the reaction of the free phenolic compounds with sulfurtrioxide complexed with an amine such as pyridine, trimethylamine,triethylamine, etc. Sulfamates can be prepared by treating the freephenolic compound with the desired amino or alkylamino or dialkylaminosulfamyl chloride in the presence of a suitable base such as pyridine.Sulfate esters can be prepared by reaction of the free phenol with thedesired alkanesulfonyl chloride in the presence of a suitable base suchas pyridine. Additionally, this invention includes compounds containingphosphates at the phenol as well as dialkyl phosphates. Phosphates canbe prepared by reaction of the phenol with the appropriatechlorophosphate. The dialkylphosphates can be hydrolyzed to yield thefree phosphates. Phosphinates are also claimed where the phenol isreacted with the desired dialkylphosphinic chloride to yield the desireddialkylphosphinate of the phenol.

[0194] The invention includes acceptable salt forms of the substitutedindoles formed from the addition reaction with either inorganic ororganic acids. Inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric aciduseful as well as organic acids such as acetic acid, propionic acid,citric acid, maleic acid, malic acid, tartaric acid, phthalic acid,succinic acid, methanesulfonic acid, toluenesulfonic acid,napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid areuseful. It is known that compounds possessing a basic nitrogen can becomplexed with many different acids (both protic and non-protic) andusually it is preferred to administer a compound of this invention inthe form of an acid addition salt. Additionally, this invention includesquaternary ammonium salts of the compounds herein. These can be preparedby reacting the nucleophilic amines of the side chain with a suitablyreactive alkylating agent such as an alkyl halide or benzyl halide.

[0195] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the extent ofthe malady and the individual being treated and will be subject to thejudgement of the medical practitioner involved. It is preferred that theadministration of one or more of the SSRIs and substituted indolecompounds herein begin at a low dose and be increased until the desiredeffects are achieved.

[0196] Effective administration of these compounds may be given at aneffective dose of from about 0.1 mg/day to about 500 mg/day. Preferably,administration will be from about 1 mg/day to about 200 mg/day in asingle dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, parenterally(including intravenous, intraperitoneal and subcutaneous injections),and transdermally. For the purposes of this disclosure, transdermaladministrations are understood to include all administrations across thesurface of the body and the inner linings of bodily passages includingepithelial and mucosal tissues. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0197] When the active ingredient in the formulations and methods ofthis invention is 1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol, alsoknown as TSE-424, or a pharmaceutically acceptable salt thereof, thepreferred daily dosage for oral delivery is from about 0.1 to about 50mg, preferably from about 2.5 to about 40 mg per day.

[0198] When the active ingredient in the formulations and methods ofthis invention is2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol,also known as ERA-923, or a pharmaceutically acceptable salt formthereof, the preferred daily dosage for oral delivery is from about 0.1to about 200 mg, preferably from about 2.5 to about 100 mg per day.

[0199] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0200] The SSRI compounds of these methods may be administered inregimens and at dosages known in the art. For instance, venlafaxinehydrochloride, which is sold by Wyeth-Ayerst Laboratories under theEffexor® name, has a recommended initial dosage of 75 mg per day, whichmay be increased to a final daily dosage of up to 225 mg. Averageadministration is from about 140 to about 180 mg per day. Fluoxetinehydrochloride, marketed by Dista Products Division of Eli Lilly andCompany under the Prozac® brandname, may be administered at a dailydosage of from about 20 to about 80 mg. Paroxetine hydrochloride,offered by SmithKline Beecham, Inc. under the Paxil® name, has arecommended daily dosage of from 20 to 50 mg. Sertraline hydrochloride,sold under the Zoloft® name by Pfizer, Inc. may be administered at aninitial dose of 25 mg per day and raised to a daily dose of from 50 to200 mg. Fluvoxamine maleate, sold under the Luvox® tradename by SolvayPharmaceuticals, Inc., may be given at a starting dose of 50 mg andraised to a daily dosage range of from 100 to 300 mg/day.

[0201] The joint administration of the two groups of compounds in thesemethods will be determined by a medical professional based upon thecondition of the recipient and the malady for which the prophylaxis ortreatment is provided. Administration of the two compounds may beginsimultaneously or one may be introduced into an ongoing regimen of theother.

[0202] Preferably, the pharmaceutical compositions of the methods hereinare supplied in unit dosage form, e.g. as tablets or capsules. In suchform, the composition is sub-divided in unit dose containing appropriatequantities of the active ingredient; the unit dosage forms can bepackaged compositions, for example, packeted powders, vials, ampoules,prefilled syringes or sachets containing liquids. The unit dosage formcan be, for example, a capsule or tablet itself, or it can be theappropriate number of any such compositions in package form.

[0203] The substituted indole compound(s) and the SSRI(s) of the presentformulations may be administered in separate dosage units, such asseparate pills, tablets, powders, etc., or combined into oneformulation. When optimum dosages for the indole compounds and the SSRIof these formulations have been determined, it may preferable toincorporate both into a single formulation for ease of administration.It is also understood that the formulations herein may or may notinclude other pharmaceutically active components.

[0204] This invention also includes kits or packages of pharmaceuticalformulations designed for use in the regimens and methods describedherein. These kits are preferably designed for daily oral administrationover the specified term or cycle of administration, preferably for thenumber of prescribed oral administrations per day, and organized so asto indicate a single oral formulation or combination of oralformulations to be taken on each day of the regimen or cycle. Preferablyeach kit will include oral tablets to be taken on each the daysspecified, in some embodiments one oral tablet will contain each of thecombined daily dosages indicated and in other embodiments theadministrations of the separate compounds will be present in separateformulations or compositions. It is most preferable that the package orkit shall have a calendar or days-of-the-week designation directing theadministration of the appropriate compositions on the appropriate day ortime.

[0205] A preferred combination of this invention includes pharmaceuticalcompositions of1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol,or a pharmaceutically acceptable salt thereof, packaged and/or utilizedin combination with venlafaxine, or a pharmaceutically acceptable saltthereof. Another comprises2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-ol,or pharmaceutically acceptable salt thereof, packaged and/or used incombination with venlafaxine, or a pharmaceutically acceptable saltthereof.

[0206] Solid oral formulations, preferably in the form of a film coatedtablet or capsule, useful for this invention include the activesubstituted indole pharmacological agents disclosed herein incombination with carrier or excipient systems having the components:

[0207] a) a filler and disintegrant component comprising from about 5%to about 82% by weight (wght) of the total formulation, preferablybetween about 30% and about 80% of the formulation, of which from about4% to about 40% by weight of the total formulation comprises one or morepharmaceutically acceptable disintegrants;

[0208] b) optionally, a wetting agent comprising from about 0.2 to about5% of the composition (wght), such as selected from the group of sodiumlauryl sulfate, polyoxyethylene sorbitan fatty acid esters,polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethyleneglycols, polyoxyethylene castor oil derivatives, docusate sodium,quaternary ammonium compounds, sugar esters of fatty acids andglycerides of fatty acids;

[0209] c) a lubricant comprising from about 0.2% to about 10% of thecomposition (wght), such as selected from the group of magnesiumstearate or other metallic stearates (e.g. calcium stearate or zincstearate), fatty acid esters (e.g. sodium stearyl fumarate), fatty acids(e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oil,parrafins, hydrogenated vegetable oils, leucine, polyethylene glycols,metallic lauryl sulfates and sodium chloride; and

[0210] d) optionally, a glidant comprising from about 0.1% to about 10%(wght) of the composition, the glidant selected from those known in theart, including from the group of silicon dioxide, talc, metallicstearates, calcium silicate, or metallic lauryl sulfates.

[0211] While the formulations described herein may be used in anuncoated or non-encapsulated solid form, preferably the finalcompositions are coated or encapsulated. The pharmacologicalcompositions may be optionally coated with a film coating, preferablycomprising from about 0.3% to about 8% by weight of the overallcomposition. Film coatings useful with the present formulations areknown in the art and generally consist of a polymer (usually acellulosic type of polymer), a colorant and a plasticizer. Additionalingredients such as wetting agents, sugars, flavors, oils and lubricantsmay be included in film coating formulations to impart certaincharacteristics to the film coat. The compositions and formulationsherein may also be combined and processed as a solid, then placed in acapsule form, such as a gelatin capsule.

[0212] The filler component listed above may utilize the filler orbinder components known in the art for solid oral formulations.Pharmaceutically acceptable fillers or binding agents selected fromthose known in the art including, but not limited to, lactose,microcrystalline cellulose, sucrose, mannitol, calcium phosphate,calcium carbonate, powdered cellulose, maltodextrin, sorbitol, starch,or xylitol.

[0213] In conjunction with or in place of the materials listed above forthe filler component, the present formulations utilize disintegrantagents. These disintegrants may be selected from those known in the art,including pregelatinized starch and sodium starch glycolate. Otheruseful disintegrants include croscarmellose sodium, crospovidone,starch, alginic acid, sodium alginate, clays (e.g. veegum or xanthangum), cellulose floc, ion exchange resins, or effervescent systems, suchas those utilizing food acids (such as citric acid, tartaric acid, malicacid, fumaric acid, lactic acid, adipic acid, ascorbic acid, asparticacid, erythorbic acid, glutamic acid, and succinic acid) and an alkalinecarbonate component (such as sodium bicarbonate, calcium carbonate,magnesium carbonate, potassium carbonate, ammonium carbonate, etc.). Thedisintegrant(s) useful herein will comprise from about 4% to about 40%of the composition by weight, preferably from about 15% to about 35%,more preferably from about 20% to about 35%. Some components may havemultiple functions in the formulations of this invention, acting e.g. asboth a filler and a disintegrant, such a component may be referred to asa filler disintegrant and its function in a specific formulation may besingular even though its properties may allow multiple functionality.

[0214] The pharmaceutical formulations and carrier or excipient systemsherein preferably also contain an antioxidant or a mixture ofantioxidants, most preferably ascorbic acid. Other antioxidants whichmay be used include sodium ascorbate and ascorbyl palmitate, preferablyin conjunction with an amount of ascorbic acid. A preferable range forthe antioxidant(s) is from about 0.5% to about 15% by weight, mostpreferably from about 0.5% to about 5% by weight.

[0215] Among the formulations of this invention are pharmaceuticalformulations containing a pharmaceutically effective amount of an activepharmacological agent and a carrier or excipient system comprising:

[0216] a) a filler and disintegrant component comprising between about50% and about 87% of the formulation, with from about 4% to about 40% ofthe formulation comprising one or more disintegrant agents;

[0217] b) a wetting agent comprising between about 0.5% and about 2.7%of the formulation;

[0218] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation;

[0219] and

[0220] d) a glidant comprising between about 0.1% and about 5.5% of theformulation.

[0221] The percentages listed in the formulations above indicatepercentages by weight of the total weight of the components listed froma) to d). The formulations above also preferably contain an optionalantioxidant component, preferably ascorbic acid, at a concentration offrom about 0.5% to about 5.5% by weight of the formulation. Theformulations are also preferably contained within a pharmaceuticallyacceptable capsule, such as a gel capsule, or coated with a film coatingcomprising from about 0.3% to about 8% by weight of the formulation.

[0222] This invention also comprises a pharmaceutical carrier orexcipient systems useful in pharmaceutical compositions utilizing as anactive ingredient one or more of the compounds described herein, or apharmaceutically acceptable salt thereof, as described herein. Thesepharmaceutical carrier or excipient systems comprise, by weight:

[0223] a) a filler and disintegrant component comprising between about54% and about 80% of the formulation, with the disintegrant agent(s)therein comprising from about 4% to about 40% by weight of the overallformulation;

[0224] b) a wetting agent comprising between about 0.55% and about 2.5%of the formulation;

[0225] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation;

[0226] and

[0227] d) a glidant comprising between about 0.1% and about 5.0% of theformulation.

[0228] The more preferred carrier or excipient systems above alsooptionally and preferably contain an antioxidant component, preferablyascorbic acid, at a concentration of from about 0.1% to about 5.0% byweight.

[0229] Among the carrier or excipient systems of this invention arethose comprising:

[0230] a) a filler and disintegrant component, as described above,comprising between about 50% and about 87% of the formulation, thedisintegrant(s) therein comprising from about 25% to about 35% of theformulation, by weight;

[0231] b) a wetting agent comprising between about 0.55% and about 2.7%of the formulation;

[0232] c) a lubricant comprising between about 0.2% and about 5.5% ofthe formulation;

[0233] d) a glidant comprising between about 0.1% and about 5.5% of theformulation; and

[0234] e) an antioxidant component, preferably ascorbic acid, at aconcentration of from about 0.1% to about 5.5% by weight.

EXAMPLE 1

[0235] TSE-424 Acetate-Rapid Dissolution Formulations without withAscorbic Ascorbic Ingredient Acid Acid TSE-424 acetate, 10.00 10.00micronized* Lactose NE fast flow 33.10 31.60 Microcrystalline 25.0025.00 Cellulose, NF (Avicel PH101) Starch 1500 20.00 20.00 Sodium LaurylSulfate 1.50 1.50 NF Sodium Starch Glycolate 10.00 10.00 Ascorbic AcidUSP — 1.5 Syloid 244 FP 0.15 0.15 Magnesium Stearate 0.25 0.25

[0236] The formulations given above in Table 1 were prepared byincorporating a portion of the excipients in the granulation and aportion is also added in the final blending steps as dry powders. Adissolution profile generated for the formulations demonstrated almost90% release of the drug in 30 minutes. Thus, the unique combination ofdisintegrants and soluble diluents plus the incorporation of bothgranulated and powdered solids into the composition ensures the fastestrelease of drug.

[0237] Wet granulation of the formulations as described in Table 1 maybe carried out by mixing the drug and ascorbic acid with a portion ofthe lactose, microcrystalline cellulose, pregelatinized starch andsodium starch glycolate. The sodium lauryl sulfate is dissolved in thewater and used to granulate the mixture of powders in a high shearmixer. The granulation is dried in a fluid bed dryer to a moisture of2-3%. The particle size of the dried granulation is controlled bypassing through a mill equipped with knife-edged blades and using a 20-or 30-mesh screen. The silicon dioxide and remaining lactose,microcrystalline cellulose, pregelatinized starch, and sodium starchglycolate are mixed with the milled granulation in a tumble-type mixer.The final blend is prepared by adding magnesium stearate to thetumble-type mixer and mixing. Compression is carried out on a rotarytablet press using appropriate size tooling. Coating is performed inconventional coating pans and applying the coating suspension to achievea suitable film coat.

EXAMPLE 2

[0238] Modified TSE-424 Formulation % w/w 5% Ingredient granulationTSE-424 acetate, micronized^(a) 5.00 Lactose NF 41.00 MicrocrystallineCellulose, NF 35.00 Pregelatinized Starch NF 10.00 Sodium Lauryl SulfateNF 1.50 I-Ascorbic Acid USP 1.50 Sodium Starch Glycolate NF 5.50Magnesium Stearate NF 0.50 Pur. Water USP^(b) qs

EXAMPLE 3

[0239] ERA-923 Formulations % w/w 10.86% 11.19% 17.5% 17.9% granula-granula- granula- granula- Ingredient tion tion tion tion ERA-923,micronized^(a) 10.867 11.193 17.489 17.909 Lactose NF 29.000 29.00017.380 18.000 Microcrystalline Cellulose, 40.633 42.807 38.000 39.090 NFPregelatinized Starch NF 10.000 10.000 14.630 15.000 Sodium LaurylSulfate NF 2.500 — 2.500 — I-Ascorbic Acid USP 1.500 1.500 1.500 1.500Sodium Starch Glycolate 5.000 5.000 8.000 8.000 NF Magnesium Stearate NF0.500 0.500 0.500 0.500 Pur. Water USP^(b) qs qs qs qs

[0240] ERA-923 tablets are compressed to a tablet weight of up to 640 mgto achieve the target dose (up to 100 mg). Tablets may then be filmcoated.

EXAMPLE 4

[0241] TSE-424 at 5% Granulation

[0242] A preferred carrier or excipient system for formulating agranulation of from about 2 to about 8% by weight of one of the activepharmacological agents of this invention, preferably about 5%, may beproduced utilizing the carrier or excipient components on a weightpercentage; lactose from about 32% to about 38%, microcrystallinecellulose from about 32% to about 38%, pregelatinized starch from about12% to about 16%, ascorbic acid from about 1% to about 2%, sodium laurylsulfate from about 1% to about 2%, sodium starch glycolate from about 4%to about 8%, silicon dioxide from about 0.1% to about 0.2% and magnesiumstearate from about 0.3% to about 0.7%.

[0243] A formulation of this invention utilizing TSE-424 as the activeingredient at a 5% granulation was prepared utilizing the componentslisted below in a granulation part of components and a dry part. ItemNo. Ingredients Mg/Unit Granulation Part: 1 TSE-424 acetate 5.00 2Lactose NF 26.60 3 Microcrystalline Cellulose NF 25.00 4 PregelatinizedStarch NF 10.00 5 Ascorbic Acid USP 1.50 6 Sodium Lauryl Sulfate NF 1.507 Sodium Starch Glycolate NF 4.00 8 Water, Purified USP Q.S. 73.60 DryPart: 9 Lactose NF (fast flo) 9.75 10 Microcrystalline Cellulose NF10.00 11 Pregelatinized Starch NF 4.00 12 Sodium Starch Glycolate NF2.00 13 Silicon Dioxide NF 0.15 14 Magnesium Stearate NF 0.50 100.00

[0244] A film coat of White Opadry I (YS-1-18027-A) was applied to thetablets, which were compressed as follows: Dose of TSE-424 tabletweight, mg mg of film coat applied/tablet  5 mg 100 6.0 10 mg 200 8.0 20mg 400 13.0

What is claimed:
 1. A method for treatment of depression, anxiety,generalized anxiety disorder (GAD), hot flush, post partum depression,premenstrual syndrome, obesity, obsessive compulsive disorder,post-traumatic stress disorder, social phobia, disruptive behaviordisorders, impulse control disorders, borderline personality disorder,chronic fatigue disorder, premature ejaculation, pain, attention deficitdisorders, with and without hyperactivity, Gilles de la Tourettesyndrome, bulimia nervosa, or Shy Drager Syndrome in a mammal, themethod comprising administering to a mammal in need thereof apharmaceutically effective amount of a selective serotonin reuptakeinhibitor, or a pharmaceutically acceptable salt thereof, and apharmaceutically effective amount of a compound of the formulae I or II:

wherein Z is a moiety selected from the group of:

wherein: R₁ is selected from H, OH or the C₁-C₁₂ esters or C₁-C₁₂ alkylethers thereof, benzyloxy, or halogen; or C₁-C₄ halogenated ethersincluding trifluoromethyl ether and trichloromethyl ether. R₂, R₃, R₅and R₆ are independently selected from H, OH or the C₁-C₁₂ esters orC₁-C₁₂ alkyl ethers thereof, halogens, or C₁-C₄ halogenated ethers,cyano, C₁-C₆ alkyl, or trifluoromethyl, with the proviso that, when R₁is H, R₂ is not OH; R₄ is selected from H, OH or the C₁-C₁₂ esters orC₁-C₁₂ alkyl ethers thereof, halogens, or C₁-C₄ halogenated ethers,benzyloxy, cyano, C₁-C₆ alkyl, or trifluoromethyl; X is selected from H,C₁-C₆ alkyl, cyano, nitro, trifluoromethyl, halogen; n is 1, 2 or 3; Yis selected from: a) the moiety:

wherein R₇ and R₈ are independently selected from the group of H, C₁-C₆alkyl, or phenyl optionally substituted by CN, C₁-C₆ alkyl, C₁-C₆alkoxy, halogen, —OH, —CF₃, or —OCF₃; b) a five-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; c) a six-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl; d) a seven-membered saturated,unsaturated or partially unsaturated heterocycle containing up to twoheteroatoms selected from the group consisting of —O—, —NH—, —N(C₁C₄alkyl)—, —N═, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄)alkyl;; or e) a bicyclic heterocyclecontaining from 6-12 carbon atoms either bridged or fused and containingup to two heteroatoms selected from the group consisting of —O—, —NH—,—N(C₁C₄ alkyl)—, and —S(O)_(m)—, wherein m is an integer of from 0-2,optionally substituted with 1-3 substituents independently selected fromthe group consisting of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ acyloxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H—, —CN—, —CONHR₁—, —NH₂—, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂R₁—, —NHCOR₁—, —NO₂, and phenyl optionallysubstituted with 1-3 (C₁-C₄) alkyl; or a pharmaceutically acceptablesalt thereof.
 2. The method of claim 1 wherein in the compound of theformulae I or II: R₁ is selected from H, OH or the C₁-C₁₂ esters oralkyl ethers thereof, benzyloxy, or halogen; R₂, R₃, R₅, and R₆ areindependently selected from H, OH or the C₁-C₁₂ esters or alkyl ethersthereof, halogen, cyano, C₁-C₆ alkyl, or trihalomethyl; with the provisothat, when R₁ is H, R₂ is not OH; R₄ is selected from H, OH or theC₁-C₁₂ esters or alkyl ethers thereof, benzyloxy, halogen, cyano, C₁-C₆alkyl, or trihalomethyl; X is selected from H, C₁-C₆ alkyl, cyano,nitro, trifluoromethyl, halogen; Y is the moiety:

R₇ and R₈ are selected independently from H, C₁-C₆ alkyl, or combined by—(CH₂)_(p)—, wherein p is an integer of from 2 to 6, so as to form aring, the ring being optionally substituted by up to three substituentsselected from the group of hydrogen, hydroxyl, halo, C₁-C₄ alkyl,trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy (C₁-C₄)alkyl, —CO₂H, —CN,—CONH(C₁-C₄), —NH₃, C₁-C₄ alkylamino, C₁-C₄ dialkylamino, —NHSO₂(C₁-C₄),—NHCO(C₁-C₄), and —NO₃; or a pharmaceutically acceptable salt thereof.3. The method of claim 2 wherein, in the compound of the formulae I orII, the ring formed by a the combination of R₇ and R₈ by —(CH₂)_(p)— isselected from aziridine, azetidine, pyrrolidine, piperidine,hexamethyleneamine or heptamethyleneamine.
 4. The method of claim 1utilizing a compound of the formulae I or II, wherein R₁ is OH; R₂-R₆are as defined in claim 1; X is selected from the group of Cl, NO₂, CN,CF₃, or CH₃; and Y is the moiety:

and R₇ and R₈ are concatenated together as —(CH₂)_(r)—, wherein r is aninteger of from 4 to 6, to form a ring optionally substituted by up tothree substituents selected from the group of hydrogen, hydroxyl, halo,C₁-C₄ alkyl, trihalomethyl, C₁-C₄ alkoxy, trihalomethoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, hydroxy(C₁-C₄)alkyl, —CO₂H, —CN, —CONH(C₁-C₄)alkyl, —NH₂, C₁-C₄ alkylamino,di(C₁-C₄)alkylamino, —NHSO₂(C₁-C₄)alkyl, —NHCO(C₁-C₄)alkyl, and —NO₂; ora pharmaceutically acceptable salt thereof.
 5. The method of claim 1wherein the SSRI is selected from the group of venlafaxine, fluoxetine,paroxetine, sertraline, or fluvoxamine, or a pharmaceutically acceptablesalt thereof.
 6. The method of claim 1 wherein the disorder isdepression.
 7. The method of claim 1 wherein the disorder is pain. 8.The method of claim 1 wherein the disorder is generalized anxietydisorder.
 9. The method of claim 1 wherein the disorder is anxiety. 10.A method for treating depression, anxiety, generalized anxiety disorder(GAD), hot flush, post partum depression, premenstrual syndrome,obesity, obsessive compulsive disorder, post-traumatic stress disorder,social phobia, disruptive behavior disorders, impulse control disorders,borderline personality disorder, chronic fatigue disorder, prematureejaculation, pain, attention deficit disorders, with and withouthyperactivity, Gilles de la Tourette syndrome, bulimia nervosa, or ShyDrager Syndrome in a mammal, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a SSRI, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyeffective amount of a compound of the formulae I or II:

wherein R₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined in claim 1,or a pharmaceutically acceptable salt thereof.
 11. A method for treatingdepression, anxiety, generalized anxiety disorder (GAD), hot flush, postpartum depression, premenstrual syndrome, obesity, obsessive compulsivedisorder, post-traumatic stress disorder, social phobia, disruptivebehavior disorders, impulse control disorders, borderline personalitydisorder, chronic fatigue disorder, premature ejaculation, pain,attention deficit disorders, with and without hyperactivity, Gilles dela Tourette syndrome, bulimia nervosa, or Shy Drager Syndrome in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a SSRI, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically effective amount of acompound of the formulae (V) or (VI):

wherein R₁, R₂, R₃, R₄, R₅, R₆, X, and Y are as defined in claim 1, or apharmaceutically acceptable salt thereof.
 12. A method for treatingdepression, anxiety, generalized anxiety disorder (GAD), hot flush, postpartum depression, premenstrual syndrome, obesity, obsessive compulsivedisorder, post-traumatic stress disorder, social phobia, disruptivebehavior disorders, impulse control disorders, borderline personalitydisorder, chronic fatigue disorder, premature ejaculation, pain,attention deficit disorders, with and without hyperactivity, Gilles dela Tourette syndrome, bulimia nervosa, or Shy Drager Syndrome in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a SSRI, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically effective amount of acompound of the formulae VII and VIII:

wherein R₁, R₂, R₃, R₄, R₅, R₆, n, X, and Y are as defined in claim 1,or a pharmaceutically acceptable salt thereof.
 13. A method for treatingdepression, anxiety, generalized anxiety disorder (GAD), hot flush, postpartum depression, premenstrual syndrome, obesity, obsessive compulsivedisorder, post-traumatic stress disorder, social phobia, disruptivebehavior disorders, impulse control disorders, borderline personalitydisorder, chronic fatigue disorder, premature ejaculation, pain,attention deficit disorders, with and without hyperactivity, Gilles dela Tourette syndrome, bulimia nervosa, or Shy Drager Syndrome in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of 1-[4-(2-Azepan-1yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol and apharmaceutically effective amount of a SSRI, or a pharmaceuticallyacceptable salt thereof.
 14. The method of claim 14 wherein the SSRI isselected from the group of venlafaxine, fluoxetine, paroxetine,sertraline, or fluvoxamine, or a pharmaceutically acceptable saltthereof.
 15. A method for treating depression, anxiety, generalizedanxiety disorder (GAD), hot flush, post partum depression, premenstrualsyndrome, obesity, obsessive compulsive disorder, post-traumatic stressdisorder, social phobia, disruptive behavior disorders, impulse controldisorders, borderline personality disorder, chronic fatigue disorder,premature ejaculation, pain, attention deficit disorders, with andwithout hyperactivity, Gilles de la Tourette syndrome, bulimia nervosa,or Shy Drager Syndrome in a mammal, the method comprising administeringto a mammal in need thereof a pharmaceutically effective amount of2-(4-Hydroxy-phenyl)-3-methyl-1-(4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-5-oland a pharmaceutically effective amount of a SSRI, or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 16 wherein the SSRI isselected from the group of venlafaxine, fluoxetine, paroxetine,sertraline, or fluvoxamine, or a pharmaceutically acceptable saltthereof.